CLINICAL TRIAL: NONSENSE-MUTATION-MEDIATED DUCHENNE MUSCULAR DYSTROPHY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 PTC124是一种新型的口服生物利用的小分子化合物，可促进含有提前终止密码子的信使核糖核酸(MRNA)的核糖体阅读(也称为无义突变)。该药物有可能克服无义突变受试者的基因缺陷，作为杜氏肌营养不良症(DMD)和其他遗传性疾病的基础。PTC124的开发为治疗DMD提供了一种独特的策略，将对特定类型的遗传缺陷的检测与一种小分子药物相结合，这种药物有可能通过恢复缺失蛋白质的生产来安全地纠正该遗传缺陷的表型表达。 该方案描述了一项2a期、多部位、开放标记、剂量范围、有效性、安全性和药代动力学(PK)研究，研究对象为24名5岁以上的无意义突变介导的DMD患者。这项研究将作为整体开发计划的一部分进行，旨在获得监管部门的批准，将PTC124用于治疗由于Dstrophin基因的无义突变而导致的DMD患者。计划有6名受试者接受为期28天的PTC124治疗，每天3次，剂量分别为4、4和8毫克/公斤。一旦这些受试者完成了28天的治疗，数据监测委员会(DMC)为这项研究审查了这些受试者的数据，计划再招募18名受试者接受28天的PTC124治疗，TID剂量为10、10和20毫克/公斤。这项研究的计划剂量在健康志愿者之前的第一阶段多剂量试验中安全和可耐受的剂量范围内。PTC124治疗的总持续时间为28天，这得到了在大鼠和狗身上持续28天的毒理学研究结果以及来自健康志愿者14天第一阶段多剂量试验的安全性数据的支持。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PTC124 is a novel, orally bioavailable, small-molecule compound that promotes ribosomal readthrough of messenger ribonucleic acid (mRNA) containing a premature stop codon (also referred to as a nonsense mutation). The drug has the potential to overcome the genetic defect in subjects with nonsense mutations as the basis for Duchenne muscular dystrophy (DMD) and other genetic disorders. Development of PTC124 offers a unique strategy for the treatment of DMD, coupling testing for a specific type of genetic defect with a small-molecule remedy that has the potential to safely correct the phenotypic expression of that genetic defect by restoring the production of the missing protein. This protocol describes a Phase 2a, multi-site, open-label, dose-ranging, efficacy, safety, and pharmacokinetic (PK) study in 24 subjects with nonsense-mutation-mediated DMD who are greater than 5 years of age. This study will be conducted as part of an overall development program aimed at obtaining regulatory approval of PTC124 as treatment for subjects with DMD resulting from a nonsense mutation in the dystrophin gene. It is intended that 6 subjects will be enrolled to receive 28 days of treatment with PTC124, given 3 times per day (TID) at a dose of 4-, 4-, and 8-mg/kg. Once these subjects have completed 28 days of treatment and the data for these subjects have been reviewed by the Data Monitoring Committee (DMC) for the study, it is intended that 18 additional subjects will be enrolled to receive 28 days of treatment with PTC124, given TID at a dose of 10-, 10-, and 20-mg/kg. The planned doses in this study are within the dose range that was safe and tolerable in the preceding Phase 1 multiple-dose trial in healthy volunteers. The total duration of PTC124 treatment, 28 days, is supported by the results of toxicology studies of 28 days duration in rats and dogs, and safety data derived from the 14-day Phase 1 multiple-dose trial in healthy volunteers.